Several brain diseases arise from protein aggregation;fronto-temporal dementia (FTD) and Alzheimer's disease alone affect nearly 5 million Americans. Though mice model aspects of disease, they may not become ill for months or even years. Instead, cell culture systems derived from these mice may provide information about disease mechanisms in days or weeks thereby speeding discovery of disease treatment. The overall hypothesis is that generating stem cell lines carrying mutations or combinations of genes leading to diseases will provide valuable research tools to study pathogenesis. Specifically, central nervous system stem cell containing neurospheres will be investigated for their efficacy in recapitulating parent mouse strain phenotypes in vitro. Mice with mutations in the microtubule associated protein tau gene accurately model biochemical, histological, and behavioral aspects of human FTD. Prominent cellular phenotypes of disease, hyperphosphorylation and aggregation of the tau protein, can be tracked with conventional protein detection methods and will be used as markers to assess the utility of neurospheres and their differentiated progeny as models. The focus of Aim 1 is to determine if neurospheres exhibit the same mutation-specific temporal sequence of tau pathology observed in their parental strains, and investigate how proliferation, survival, and differentiation are affected by transgene expression. Results will be compared to neurospheres and mice expressing the human encoded wild type tau gene. One pitfall to mouse modeled diseases arising from tau phosphorylation events is that endogenous mouse tau may inhibit human encoded tau phosphorylation. Therefore the focus of Aim 2 is to test the hypothesis that expression of endogenous mouse tau alters human transgene-encoded tau phosphorylation and aggregation in vivo and in vitro. Both mutant and wild type human tau transgenes will be transferred to a mouse tau null background. Mice and neurospheres will be characterized and compared to corresponding mouse tau wild type lines. If neurospheres recapitulate in vivo phenotypes of their parent mouse strains, they may serve as high through-put assay systems to investigate other genes and small molecules involved in disease pathogenesis.